The antiphospholipid syndrome is a non-inflammatory autoimmune disease characterised by the presence of antiphospholipid antibodies in the plasma of patients with venous or arterial thrombosis or recurrent complications of pregnancy. The strong relation between the presence of antibodies against anionic phospholipids and thrombo-embolic complications is well established, but how the presence of antiphospholipid antibodies results in the observed clinical manifestations remains a mystery. Experimental observations suggest that an altered regulation of platelet function can cause the thrombotic complications observed in the antiphospholipid syndrome. In this review, we will discuss the evidence that the platelet is an important player in the pathogenesis of the antiphospholipid syndrome.
2 Jackson SP . The growing complexity of platelet aggregation. Blood2007; 109: 5087–5095.
3.
3 Jones CI Garner SF Angenent W . Mapping the platelet profile for functional genomic studies and demonstration of the effect size of the GP6 locus. J Thromb Haemost2007; 5: 1756–1765.
4.
4 Goldsmith HL Turitto VT . Rheological aspects of thrombosis and haemostasis: basic principles and applications. ICTH-Report–Subcommittee on Rheology of the International Committee on Thrombosis and Haemostasis. Thromb Haemost1986; 55: 415–435.
5.
5 De Groot PG Sixma JJ . Perfusion chambers. In: AD Michelson , (ed), Platelets.Academic Press; 2002. p. 347–356.
7 Turitto VT Weiss HJ Baumgartner HR . Decreased platelet adhesion on vessel segments in von Willebrand's disease: a defect in initial platelet attachment. J Lab Clin Med1983; 102: 551–564.
8.
8 Farndale RW Sixma JJ Barnes MJ de Groot PG . The role of collagen in thrombosis and hemostasis. J Thromb Haemost2004; 2: 561–573.
9.
9 Huizinga EG Tsuji S Romijn RA . Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science2002; 297: 1176–1179.
10.
10 Savage B Saldivar E Ruggeri ZM . Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell1996; 84: 289–297.
11.
11 Arai M Yamamoto N Moroi M Akamatsu N Fukutake K Tanoue K . Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency. Br J Haematol1995; 89: 124–130.
12.
12 Beumer S IJsseldijk MJ de Groot PG Sixma JJ . Platelet adhesion to fibronectin in flow: dependence on surface concentration and shear rate, role of platelet membrane glycoproteins GP IIb/IIIa and VLA-5, and inhibition by heparin. Blood1994; 84: 3724–3733.
13.
13 Weiss HJ Turitto VT Baumgartner HR . Platelet adhesion and thrombus formation on subendothelium in platelets deficient in glycoproteins IIb-IIIa, Ib, and storage granules. Blood1986; 67: 322–330.
14.
14 Gruner S Prostredna M Schulte V . Multiple integrin-ligand interactions synergize in shear-resistant platelet adhesion at sites of arterial injury in vivo. Blood2003; 102: 4021–4027.
15.
15 Savage B Cattaneo M Ruggeri ZM . Mechanisms of platelet aggregation. Curr Opin Hematol2001; 8: 270–276.
16.
16 Jackson SP Nesbitt WS Kulkarni S . Signaling events underlying thrombus formation. J Thromb Haemost2003; 1: 1602–1612.
17.
17 Weiss HJ Turitto VT Baumgartner HR . Further evidence that glycoprotein IIb-IIIa mediates platelet spreading on subendothelium. Thromb Haemost1991; 65: 202–205.
18.
18 Kulkarni S Dopheide SM Yap CL . A revised model of platelet aggregation. J Clin Invest2000; 105: 783–791.
19.
19 Ruggeri ZM . Old concepts and new developments in the study of platelet aggregation. J Clin Invest2000; 105: 699–701.
20.
20 Remijn JA Wu YP Jeninga EH . Role of ADP receptor P2Y(12) in platelet adhesion and thrombus formation in flowing blood. Arterioscler Thromb Vasc Biol2002; 22: 686–691.
21.
21 Barstad RM Orvim U Hamers MJ Tjønnfjord GE Brosstad FR Sakariassen KS . Reduced effect of aspirin on thrombus formation at high shear and disturbed laminar blood flow. Thromb Haemost1996; 75: 827–832.
22.
22 Gachet C . ADP receptors of platelets and their inhibition. Thromb Haemost2001; 86: 222–232.
23.
23 Roald HE Orvim U Bakken IJ Barstad RM Kierulf P Sakariassen KS . Modulation of thrombotic responses in moderately stenosed arteries by cigarette smoking and aspirin ingestion. Arterioscler Thromb1994; 14: 617–621.
24.
24 Clemetson KJ . A short history of platelet glycoprotein Ib complex. Thromb Haemost2007; 98: 63–68.
25.
25 Adams TE Huntington JA . Thrombin-cofactor interactions: structural insights into regulatory mechanisms. Arterioscler Thromb Vasc Biol2006; 26: 1738–1745.
26.
26 Patrono C Garcia Rodriguez LA Landolfi R Baigent C . Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med2005; 353: 2373–2383.
27.
27 Forastiero R Martinuzzo M Carreras LO Maclouf J . Anti-beta2 glycoprotein I antibodies and platelet activation in patients with antiphospholipid antibodies: association with increased excretion of platelet-derived thromboxane urinary metabolites. Thromb Haemost1998; 79: 42–45.
28.
28 Galli M Cortelazzo S Viero P Finazzi G de Gaetano G Barbui T . Interaction between platelets and lupus anticoagulant. Eur J Haematol1988; 41: 88–94.
29.
29 Campbell AL Pierangeli SS Wellhausen S Harris EN . Comparison of the effects of anticardiolipin antibodies from patients with the antiphospholipid syndrome and with syphilis on platelet activation and aggregation. Thromb Haemost1995; 73: 529–534.
30.
30 Martinuzzo ME Maclouf J Carreras LO Levy-Toledano S . Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost1993; 70: 667–671.
31.
31 Espinola RG Pierangeli SS Gharavi AE Harris EN . Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost2002; 87: 518–522.
32.
32 Orlando E Cortelazzo S Marchetti M Sanfratello R Barbui T . Prolonged bleeding time in patients with lupus anticoagulant. Thromb Haemost1992; 68: 495–499.
33.
33 Urbanus RT de Laat HB de Groot PG Derksen RH . Prolonged bleeding time and lupus anticoagulant: a second paradox in the antiphospholipid syndrome. Arthritis Rheum2004; 50: 3605–3609.
34.
34 Martinuzzo ME Maclouf J Carreras LO Levy-Toledano S . Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost1993; 70: 667–671.
35.
35 Lutters BC Meijers JC Derksen RH Arnout J de Groot PG . Dimers of beta 2-glycoprotein I mimic the in vitro effects of beta 2-glycoprotein I-anti-beta 2-glycoprotein I antibody complexes. J Biol Chem2001; 276: 3060–3067.
36.
36 Jankowski M Vreys I Wittevrongel C . Thrombogenicity of beta 2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood2003; 101: 157–162.
37.
37 Lutters BC Derksen RH Tekelenburg WL Lenting PJ Arnout J de Groot PG . Dimers of beta 2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2'. J Biol Chem2003; 278: 33831–33838.
38.
38 Riddell DR Vinogradov DV Stannard AK Chadwick N Owen JS . Identification and characterization of LRP8 (apoER2) in human blood platelets. J Lipid Res1999; 40: 1925–1930.
39.
39 Pennings MT van Lummel M Derksen RH . Interaction of beta2-glycoprotein I with members of the low density lipoprotein receptor family. J Thromb Haemost2006; 4: 1680–1690.
40.
40 Korporaal SJ Relou IA van Eck M . Binding of low density lipoprotein to platelet apolipoprotein E receptor 2' results in phosphorylation of p38MAPK. J Biol Chem2004; 279: 52526–52534.
41.
41 Shen GQ Li L Girelli D . An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction. Am J Hum Genet2007; 81: 780–791.
42.
42 Pennings MT Derksen RH Urbanus RT Tekelenburg WL Hemrika W de Groot PG . Platelets express three different splice variants of ApoER2 that are all involved in signaling. J Thromb Haemost2007; 5: 1538–1544.
43.
43 Herz J Strickland DK . LRP: a multifunctional scavenger and signaling receptor. J Clin Invest2001; 108: 779–784.
44.
44 Lillis AP Mikhailenko I Strickland DK . Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability. J Thromb Haemost2005; 3: 1884–1893.
45.
45 Wang L Wang X Laird N Zuckerman B Stubblefield P Xu X . Polymorphism in maternal LRP8 gene is associated with fetal growth. Am J Hum Genet2006; 78: 770–777.
46.
46 Ma SL Ng HK Baum L . Low-density lipoprotein receptor-related protein 8 (apolipoprotein E receptor 2) gene polymorphisms in Alzheimer's disease. Neurosci Lett2002; 332: 216–218.
47.
47 Gent J Braakman I . Low-density lipoprotein receptor structure and folding. Cell Mol Life Sci2004; 61: 2461–2470.
48.
48 Van Lummel M Pennings MT Derksen RH . The binding site in {beta}2-glycoprotein I for ApoER2' on platelets is located in domain V. J Biol Chem2005; 280: 36729–36736.
49.
49 Shi T Giannakopoulos B Yan X . Anti-beta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V. Arthritis Rheum2006; 54: 2558–2567.
50.
50 Pennings MT Derksen RH van Lummel M . Platelet adhesion to dimeric beta-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibalpha and apolipoprotein E receptor 2'. J Thromb Haemost2007; 5: 369–377.
51.
51 Raschi E Testoni C Bosisio D . Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood2003; 101: 3495–3500.
52.
52 Clark SR Ma AC Tavener SA . Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med2007; 13: 463–469.
53.
53 Vega-Ostertag M Harris EN Pierangeli SS . Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin. Arthritis Rheum2004; 50: 2911–2919.
54.
54 Canobbio I Reineri S Sinigaglia F Balduini C Torti M . A role for p38 MAP kinase in platelet activation by von Willebrand factor. Thromb Haemost2004; 91: 102–110.
55.
55 Bock HH Jossin Y Liu P . Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. J Biol Chem2003; 278: 38772–38779.
56.
56 Yap CL Anderson KE Hughan SC Dopheide SM Salem HH Jackson SP . Essential role for phosphoinositide 3-kinase in shear-dependent signaling between platelet glycoprotein Ib/V/IX and integrin alpha(IIb)beta(3). Blood2002; 99: 151–158.
57.
57 Urbanus RT Pennings MT Derksen RH de Groot PG . Platelet activation by dimeric beta(2)-glycoprotein I requires signaling via both glycoprotein Ibalpha and Apolipoprotein E Receptor 2'. J Thromb Haemost2008; 6: 1405–1412.
58.
58 Mori T Takeya H Nishioka J Gabazza EC Suzuki K . beta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface. Thromb Haemost1996; 75: 49–55.
59.
59 Shi T Iverson GM Qi JC . Beta 2-Glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: loss of inhibition by clipped beta 2-glycoprotein I. Proc Natl Acad Sci U S A2004; 101: 3939–3944.
60.
60 Sheng Y Reddel SW Herzog H . Impaired thrombin generation in beta 2-glycoprotein I null mice. J Biol Chem2001; 276: 13817–13821.
61.
61 Bancsi LF van der Linden I Bertina RM . Beta 2-glycoprotein I deficiency and the risk of thrombosis. Thromb Haemost1992; 67: 649–653.
62.
62 Hulstein JJ Lenting PJ de Laat B Derksen RH Fijnheer R de Groot PG . beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation. Blood2007; 110: 1483–1491.
63.
63 Ferrara DE Swerlick R Casper K . Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost2004; 2: 1558–1563.
64.
64 Zhou H Wolberg AS Roubey RA . Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. Blood2004; 104: 2353–2358.
65.
65 Redecha P Tilley R Tencati M . Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood2007; 110: 2423–2431.
66.
66 Girardi G Redecha P Salmon JE . Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med2004; 10: 1222–1226.
67.
67 Galli M Reber G de Moerloose P de Groot PG . Invitation to a debate on the serological criteria that define the antiphospholipid syndrome. J Thromb Haemost2008; 6: 399–401.
68.
68 Hasselaar P Derksen RH Blokzijl L . Risk factors for thrombosis in lupus patients. Ann Rheum Dis1989; 48: 933–940.
